Skin is composed of the epidermis and the dermis. Below these layers lies the hypodermis, which is not usually classified as a layer of skin. The hypodermis is also commonly referred to as subcutaneous fat layer, sub-cutis or subcutaneous tissue. The outermost epidermis is made up of stratified squamous epithelium with an underlying basement membrane. It contains no blood vessels, and is nourished by diffusion from the dermis. The epidermis is mainly composed of keratinocytes, with melanocytes and Langerhans cells also present. This layer of skin functions as a barrier between the body and the external environment, keeping water in the body and preventing penetration of harmful chemicals and pathogens.
The dermis lies below the epidermis and contains a number of structures including blood vessels, nerves, hair follicles, smooth muscle, glands and lymphatic tissue. The dermis (or corium) is typically 0.1-3 mm thick and is the major component of human skin. It is composed of a network of connective tissue, predominantly collagen fibrils providing support and elastin fibers providing flexibility. The main cell types composing the dermis are fibroblasts, adipocytes (fat storage) and macrophages.
The hypodermis lies below the dermis and is important for attaching the skin to the underlying bone and muscle as well as supplying it with blood vessels and nerves. The hypodermis is made up of loose connective tissue and elastin and contains fibroblasts, macrophages and adipocytes. The adipocytes play a major role in the fat storage function of the hypodermis. The fat serves as a filling material and as insulation of the body from the external environment.
Facial aging occurs as the result of several factors, among them are inherent changes within the skin, effects of gravity, activity of facial muscles leading to the formation of dynamic lines, skin loss or shift, bone loss, loss of tissue elasticity and exposure to harsh environmental conditions, particularly the sun or ultraviolet radiation and pollutants. The skin ages when the epidermis begins to thin, causing the junction with the dermis to flatten. Collagen decreases as a person ages and the bundles of collagen, which gives the skin turgor, become looser and lose strength. When the skin loses elasticity, it is less able to resist stretching. Coupled with gravity, muscle pull and tissue changes, the skin begins to wrinkle Water loss and breakdown of bonds between cells also reduces the barrier function of the skin, which can cause the skin's pore size to increase.
There have been efforts to develop and use compositions to correct defects in skin, such as scars and wrinkles, or to augment the tissue of a subject in order to improve the appearance of the skin, particularly facial skin.
Currently, there are dozens of known dermal filling agents for skin augmentation which include autologous implantable materials, allogeneic products, xenogeneic products and synthetically derived products. Available dermal fillers comprise biodegradable natural substances (such as collagen, gelatine, hyaluronic acid, dextran and dried acellular particulate dermal matrix), biodegradable synthetic polymers (such as poly-L-lactic acid, polyethylene oxide and carboxymethylcellulose), non-biodegradable synthetic polymers (such as polymethyl methacrylate, polyacrylamide, polyalkylimide and silicones) and combinations thereof.
Biocompatible ceramic skin augmentation materials, such as hydroxyapatite, are known to be efficient skin augmentation materials due to their properties:
Hydroxyapatite (Ca5(PO4)3(OH)) is a naturally occurring mineral form of calcium phosphate. Hydroxyapatite comprises the mineral constituent of bone, therefore rendering it biocompatible and non-immunogenic when introduced into the body of a subject. Of note, Hydroxyapatite is biodegradable following the same metabolic pathways as bone debris resulting from common bone fractures, yet is semi-permanent, as it lasts up to 3 years when implanted into a subject. Moreover, when injected as small microspheres, Hydroxyapatite acts as a scaffold that promotes new tissue formation similar to its surrounding environment. Inside skins such as the dermis, deposited particles of Hydroxyapatite support fibroblastic ingrowth and new collagen formation (Jacovella, P. F, Clin. Interv. Aging., 2008, 3(1): 161-174, Suchanek W. and Yoshimura M., J. Mater. Res., 1997, 13(1): 94-117).
International Publication No. WO/1993/016657 discloses injectable ceramic implant compositions for soft and hard tissue repair and augmentation.
U.S. Pat. No. 7,655,250 discloses a composition for skin application, comprising sintered macroporous hydroxyapatite particles as an absorbance enhancing material.
U.S. Patent Application 2011/0125288 discloses particles of a biocompatible ceramic material in a gel carrier. The biocompatible ceramic material may be hydroxylapatite, polystyrene, polymethylmethacrylate, glass, and stainless steel. Skin augmentation products are typically injected with a needle just below the surface of the skin, at the site of the wrinkle, line, or fold (or scar or subcutaneous tissue to be enhanced). The products essentially plump up the skin from beneath the upper layers of skin. Some skin augmentation products are implanted beneath the skin through an incision. In either case, the skin is cut or punctured with a needle or a scalpel type instrument to insert skin augmentation products into the desired location, and thus the procedure is performed by a trained medical professional. Application of dermal fillers by injection or implantation is uncomfortable and possibly painful to the subject, and, furthermore, requires highly trained medical professional manpower.
International Publication No. WO 2008/072229 discloses a device and methods for delivery of dermal filler compositions into the skin of a subject using a microneedle device.
U.S. Pat. No. 8,167,852 discloses a microneedle device which includes microneedles that can be inserted into skin and dissolve or swell in skin.
It is thus desirable to have highly efficient means for painless self-administration of long lasting skin augmentation products.